Differential GLP-1R Binding and Activation by Peptide and Non-peptide Agonists

Mol Cell. 2020 Nov 5;80(3):485-500.e7. doi: 10.1016/j.molcel.2020.09.020. Epub 2020 Oct 6.


Peptide drugs targeting class B1 G-protein-coupled receptors (GPCRs) can treat multiple diseases; however, there remains substantial interest in the development of orally delivered non-peptide drugs. Here, we reveal unexpected overlap between signaling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist PF 06882961 and GLP-1 that was not observed for another compound, CHU-128. Compounds from these patent series, including PF 06882961, are currently in clinical trials for treatment of type 2 diabetes. High-resolution cryoelectron microscopy (cryo-EM) structures reveal that the binding sites for PF 06882961 and GLP-1 substantially overlap, whereas CHU-128 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not CHU-128, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs.

Keywords: G-protein-coupled receptor; GLP-1; cryoelectron microscopy; glucagon-like peptide-1 receptor; non-peptide agonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / physiology
  • Cryoelectron Microscopy / methods
  • Glucagon-Like Peptide 1 / chemistry
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Glucagon-Like Peptide-1 Receptor / chemistry
  • Glucagon-Like Peptide-1 Receptor / metabolism*
  • Humans
  • Peptides / chemistry
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship


  • Glucagon-Like Peptide-1 Receptor
  • Peptides
  • Receptors, G-Protein-Coupled
  • Glucagon-Like Peptide 1